Phase i clinical, pharmacokinetic, and pharmacodynamic study of KOS-862 (Epothilone D) in patients with advanced solid tumors and lymphoma Journal Article


Authors: Konner, J.; Grisham, R. N.; Park, J.; O'Connor, O. A.; Cropp, G.; Johnson, R.; Hannah, A. L.; Hensley, M. L.; Sabbatini, P.; Mironov, S.; Danishefsky, S.; Hyman, D.; Spriggs, D. R.; Dupont, J.; Aghajanian, C.
Article Title: Phase i clinical, pharmacokinetic, and pharmacodynamic study of KOS-862 (Epothilone D) in patients with advanced solid tumors and lymphoma
Abstract: Purpose To determine the maximum tolerated dose and safety of the epothilone, KOS-862, in patients with advanced solid tumors or lymphoma. Patients and Methods Patients were treated weekly for 3 out of 4 weeks (Schedule A) or 2 out of 3 weeks (Schedule B) with KOS-862 (16.120 mg/m2). Pharmacokinetic (PK) sampling was performed during cycles 1 and 2; pharmacodynamic (PD) assessment for microtubule bundle formation (MTBF) was performed after the 1st dose, only at or above 100 mg/m2. Results Thirty-two patients were enrolled, and twenty-nine completed ≥1 cycle of therapy. Dose limiting toxicity [DLT] was observed at 120 mg/m2. PK data were linear from 16 to 100 mg/m2, with proportional increases in mean Cmax and AUCtot as a function of dose. Full PK analysis (mean±SD) at 100 mg/m2 revealed the following: half-life (t.)=9.1± 2.2 h; volume of distribution (Vz)=119±41 L/m2; clearance (CL)=9.3±3.2 L/h/m2. MTBF (n=9) was seen in 40% of PBMCs within 1 h and in 15% of PBMC at 24-hours post infusion at 100 mg/m2. Tumor shrinkage (n=2, lymphoma), stable disease >3 months (n=5, renal, prostate, oropharynx, cholangiocarcinoma, and Hodgkin lymphoma), and tumor marker reductions (n=1, colorectal cancer/CEA) were observed. Conclusion KOS-862 was well tolerated with manageable toxicity, favorable PK profile, and the suggestion of clinical activity. The maximum tolerated dose was determined to be 100 mg/m2 weekly 3-on/1-off. MTBF can be demonstrated in PBMCs of patients exposed to KOS-862. © 2012 Springer Science+Business Media, LLC.
Keywords: adult; aged; middle aged; neoplasms; leukocytes, mononuclear; lymphoma; microtubules; solid tumors; epothilones; epothilone d; tubulin modulators; epothilone; kos-862
Journal Title: Investigational New Drugs
Volume: 30
Issue: 6
ISSN: 0167-6997
Publisher: Springer  
Date Published: 2012-12-01
Start Page: 2294
End Page: 2302
Language: English
PUBMED: 22072399
PROVIDER: scopus
DOI: 10.1007/s10637-011-9765-7
PMCID: PMC4003559
DOI/URL:
Notes: --- - "Export Date: 1 May 2013" - "CODEN: INNDD" - ":doi 10.1007/s10637-011-9765-7" - ": Chemicals/CASEpothilones; Tubulin Modulators; desoxyepothilone B" - "Source: Scopus"
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. Jason Konner
    156 Konner
  2. Paul J Sabbatini
    262 Sabbatini
  3. Svetlana Mironov
    37 Mironov
  4. Jae Hong Park
    357 Park
  5. Rachel Nicole Grisham
    170 Grisham
  6. Martee L Hensley
    290 Hensley
  7. David Hyman
    354 Hyman
  8. David R Spriggs
    325 Spriggs